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Biochemistry
C4 is one of the two complement proteins routinely measured alongside C3, but it earns a separate, specific reason for testing beyond lupus monitoring: it's the standard first screening test for hereditary angioedema, a genetic condition causing recurring episodes of severe swelling without hives, caused by a missing or malfunctioning complement regulator called C1 inhibitor. In that condition, C4 tends to run persistently low, even between attacks, which is what makes it a useful, low-cost screening step before moving to more specific and more expensive testing. Like C3, it also drops during an active lupus flare, and the two proteins are generally read together rather than one at a time.
The test reports C4 concentration in a blood sample; one commonly cited reference range lists normal C4 as roughly 15 to 45 mg/dL, though ranges vary by lab. In hereditary angioedema, C4 is low on most testing occasions, giving the screening test a sensitivity researchers have put at around 81 percent, useful, but not reliable enough on its own to rule the condition out with a single normal result. In lupus, a low C4 alongside a low C3 supports active disease, in the same way it does for C3 tested alone.
C4 plays a specific role early in one branch of the complement cascade, the branch triggered when antibodies bind to a target, which is part of why it behaves somewhat differently from C3 despite the two being tested together.
Hereditary angioedema is caused by a missing or poorly functioning C1 inhibitor, a protein that normally keeps this branch of the complement cascade in check. Without enough working C1 inhibitor, C4 gets consumed continuously, so it tends to sit low most of the time, not only during an active swelling attack, which is what makes it useful as an inexpensive first screening step, well before a more specific and costlier C1 inhibitor test is ordered.
One study following genetically confirmed hereditary angioedema patients found C4 came back within the normal range on a meaningful number of testing occasions, even in people not currently having an attack, a sensitivity researchers put at around 81 percent for untreated patients. Because of that gap, doctors are advised to go on to C1 inhibitor testing when clinical suspicion is strong, rather than stopping at a normal C4 result alone.
Outside hereditary angioedema, C4 is read alongside C3 for the same reasons C3 is tested, mainly tracking lupus activity, since both tend to fall together during an active flare.
In this condition, a missing or poorly functioning C1 inhibitor lets C4 get consumed continuously, so it tends to sit low most of the time, making it a useful, low-cost first screening test.
Not reliably on its own. Research has found C4 comes back normal on some testing occasions even in confirmed cases, so a strong clinical suspicion still warrants further testing.
A more specific test measuring C1 inhibitor level and function is usually the next step to confirm hereditary angioedema.
Yes. C4 tends to fall together with C3 during an active lupus flare, so the two are generally tested and interpreted together.
This page is general information about the test, not medical advice. Your own report's reference ranges apply — please discuss your results with your doctor.
Because the underlying C1 inhibitor problem is present all the time, not only during a swelling episode, C4 consumption tends to continue even when someone isn't currently having an attack.
It's often ordered together with C3, since reading both together gives more diagnostic information than either result alone, though the specific reason for testing can shift which one a doctor focuses on.